This project will explore two interrelated hypotheses about the etiology of Parkinson's disease: 1) that gene defects which cause improper processing of proteins can lead to loss of function and death of dopaminergic neurons; and, 2) that some of the same genes and cellular events are involved in both dystonia and Parkinson's disease. The hypotheses derive from observations by others that Parkinson's disease can be caused by defective processing of alpha-synuclein or by disruption of a ubiquitin-like protein, parkin, believed to be involved in protein processing; and by ourselves, that most cases of early onset dystonia are due to a specific change in a novel member of the Heat Shock Protein (HSP) 100/ ClP ATPase chaperonin which function in correct folding of proteins as well as degradation of proteins denatured by thermal or chemical stress. We will evaluate mutations in members of the torsin gene family and related genes, including alpha-synuclein and parkin, in a large cohort of typical Parkinson patients. The coding region of these regions will be evaluated both at the RNA and genomic DNA levels by PCR, SSCP and direct sequencing. The effect of polymorphic variations on affected status will be assessed in sib-pairs, and Parkinson disease families linked to chromosome 2p. Linkage analysis will be carried out to determine the chromosomal location of the gene responsible for rapid onset dystonia with parkinsonism (RDP) in which symptoms are frequently precipitated by stress. Candidate genes in the linked region will be evaluated for mutations and if the genomic region can be reduced to 1-2 cM we will undertake positional cloning of this disease gene. This project will also provide materials and expertise to other projects in the Center to determine cellular and state-dependent expression patterns of torsin genes in normal and transgenic mice, as well as in control and Parkinson disease brains; and the effect of mutant torsins and alpha-synucleins in altering morphology and stress responses in cultured neurons. Transgenic mice with mutations in the torsinA gene will be evaluated for consequences to neuronal plasticity and activity patterns in the mouse striatum under motoric learning paradigms.